MONOPHASIC LIQUID DOSAGE FORM
Syllabus
Definition and account of
oral solutions, syrups and elixirs.
Their importance in the
Medical field.
Components of the
formulations with examples: Solvents, buffers, sweeteners, acidifiers, flavors,
and preservatives.
Development of the formula.
Preparation , equipment in
industrial scale.
Question s
1.
Short note on preservatives in pharmaceutical dosage
forms. (98) 4
2.
Short note on syrups. (98) 4
3.
Give the importance of colorants, sweeteners,
solvents, stabilizers, flavoring agents in pharmaceutical dosage forms. (98) 4 x 4
4.
Discuss the preformulatory and informulatory aspect
of designing a multivitamin syrup. 16
5.
What are syrups? Write about the preparation,
properties and uses of at least two medicated syrups. (93) 10
6.
Differentiate between solution and elixirs. (95) 8
7.
Classify organoleptic compounds with examples. (93) 10
Solution
In pharmaceutical terms, solutions are liquid preparations that
contains one or more chemical substances dissolved in a suitable solvent or
mixture of mutually miscible solvents.
Classification
of solution
(i) According to the route
of administration
a)
Oral solutions—through oral
route.
b)
Otic solutions—instilled in the
ears.
c)
Ophthalmic
solution—instilled in the eyes.
d)
Topical solutions—applied over the
skin surface.
(ii) According to
composition and uses
a)
Syrup—aqueous solution
containing sugar.
b)
Elixir—sweetened
hydroalcoholic (combination of water and ethanol) solution.
c)
Spirit—Solution of
aromatic materials in alcohol.
d)
Aromatic Water—Solution of
aromatic material in water.
e)
Tincture / Fluid
extract—Solution prepared by extracting active constituents from crude drugs.
e.g. Compound cardamom tincture. They may also be solutions of chemical
substances dissolved in alcohol or in hydroalcoholic solvent. e.g. Tincture of
Iodine.
f)
Injection—Certain solution
prepared to be sterile and pyrogen-free and intended for parenteral
administration.
Formulation
Consideration
1) Solubility
a)
pH
b)
Cosolvency
c)
Solubilization
d)
Complexation
e)
Hydrotrophy
f)
Chemical modification of the drug molecule
2) Preservation
a)
Preservatives
b)
Antioxidants
c)
Reducing agents
d)
Synergists
|
3) Organoleptic consideration
a) Sweetening
agents
b) Flavoring
agents
c) Coloring agents
d) Viscosity
control
e) Overall
appearance
4) Stability
a) Chemical
stability
b) Physical
stability
|
SOLUBILITY
When a solid solute is
dissolved in a liquid solvent two types of interactions are evident—one is the
intra-molecular force between the solute molecules and the other is the
intermolecular force between the solute and solvent molecules. When a solute
dissolves, the substance’s intra-molecular forces (cohesive force) must be
overcome by the force of attraction between the solute and solvent molecules
(adhesive force).This involves breaking the solute-solute forces and the
solvent-solvent forces to achieve the solute-solvent forces attraction.
Expression of solubility
According
to Indian Pharmacopoeia
Descriptive Phrase
|
Approximate quantities(ml) of solvent by
volume for 1 part (1 gm) of solute by weight
|
Very soluble
Freely soluble
Soluble
Sparingly soluble
Slightly soluble
Very slightly soluble
Practically insoluble
|
less than 1 part
from 1 to 10 parts
from 10 to 30 parts
from 30 to 100 parts
from 100 to 1000 parts
from 1000 to 10,000 parts
more than 10,000 parts
|
Solubility
The solubility of an agent in
a particular solvent indicates the maximum
concentration to which a solution may be prepared with that agent and that
solvent.
Determination
of Equilibrium Solubility of a Drug
An excess of the
drug ( finely powdered to minimize the time required to attain the equilibrium)
is placed in a vial along with a specific amount of the solvent. The tightly
closed vial is then agitated at constant temperatures (preferably at
temperature somewhat higher than room temperature e.g. 300C so that
constant conditions can be maintained regardless of normal laboratory
temperature variations), and the amount of drug in solution is determined
periodically by assay (by some chemical method) of a filtered sample of the
supernate. Equilibrium is not achieved until at least two successive samplings
give the same result.
The solubility is generally expressed in mg
of solute per ml of solvent at 250 C or per 100 ml etc.
Solubility of a drug
depends on temperature, solvent, pH and the chemical nature of the molecule
itself. By modifying these parameters the solubility of a drug can be
manipulated according to the requirement of designing the dosage form.
pH
A large number of drugs are
either weak acids or weak bases. The solubility of these agents can be markedly
influenced by the pH of the environment. When a weakly acidic drug is dissolved
in water it can remain in three states, namely undissolved, dissolved and
ionized which can be expressed in the following reaction format:
The relationship between equilibrium solubility of a weakly acidic drug
and the pH of the environment can be expressed by Henderson-Hasselbach
equation:
where pKa = Dissociation
constant of the acid
[D-] = Molar
concentration of ionized drug
[DH] = Molar
concentration of unionized drug
The same equation can be written in the following forms:
where DH = Acid
D- =
Corresponding base of the acid (DH)
Weak Acid
|
Weak Base
|
 
DH = acid
D - =
corresponding base of DH
|
 
DOH = base
D+ =
corresponding acid of the base DOH
|
To maintain the drug
in soluble state the solution of a drug must be done in a suitable buffer
solution. The buffer must have the following properties:
1.
The buffer must have adequate capacity in the
desired pH range.
2.
The buffer must be biologically safe for the
intended use.
3.
The buffer (or its pH range) must have minimum
interference on the stability of the final product.
4.
The buffer should permit acceptable flavoring and
coloring of the product.
e.g. Some commonly used buffer systems are ammonium chloride, diethanol
amine, triethanolamine, boric acid, carbonic acid, phosphate buffer, glutamic
acid, tartaric acid, citric acid buffer, acetic acid buffer etc.
COSOLVENCY
Weak electrolytes and nonpolar molecules
frequently have poor water solubility. These types of solutes are more soluble
in a mixture of solvents than in one solvent alone. This phenomenon is known as
cosolvency; and the solvents that, in combination increases the
solubility of the solute are called cosolvents.
To increase the water solubility of a drug another water
miscible solvent in which the drug has good solubility is mixed.
Mechanism
of action
It has been proposed that a cosolvent system works by
reducing the interfacial tension between the predominantly aqueous solutions
and the hydrophobic solute.
Examples
of commonly used cosolvents
Ethanol, sorbitol, glycerin, propylene glycol and several
members of the polyethylene glycol polymer (PEG200) series are the limited
number of cosolvents (of water) those are used and are acceptable in oral
preparation.
Use
of cosolvents
Cosolvents are used to increase the solubility of weak
electrolytes, non-polar molecules and volatile constituents used to impart a
desirable flavor and odour to the product.
DIELECTRIC CONSTANT
One property of a solvent system is its dielectric
constant. The dielectric constant of a solvent can be defined as the ratio of
the capacitances of a capacitor filled with the solvent and air respectively.
 |
C solvent
Dielectric constant (e ) =
C air
where, C is the capacitance
of the condenser filled
with respective medium
(solvent or air)
e.g dielectric water is 78.5
Every solute shows a maximum solubility in any given
solvent system, at one or more specific dielectric constants.
To determine the relationship between solubility of a
solute with dielectric constant(s) at which maximum solubility is attained is
noted.
Pharmaceutical formulations of comparable dielectric
constant can thus be prepared, and the most appropriate solvent system can be
selected on the basis of solubility, stability and organoleptic characteristics
requirements.
SOLUBILIZATION
spontaneous increase of solubility of a poorly
water-soluble solute molecules into an aqueous solution of surface active
agents (or surfactants) in which a thermodynamically stable solution is formed.
Mechanism
When surfactants are added to water at low
concentrations, they tend to orient at the air-liquid interface.
As additional surfactant is added, the interface becomes
fully occupied, and the excess molecules are faced into the bulk of the liquid.
At still higher concentrations, the molecules of
surfactant in the bulk of the liquid begin to form oriented aggregates or
micelles, this change in orientation occurs abruptly (suddenly).
The
concentration of surface active agent at which micelles occurs is called critical
micelle concentration .
Solubilization is thought to occur by virtue of the
solute dissolving in or being adsorbed onto the micelle. The water solubility
of the solute increases with the concentration of the micelles.
Examples of some
solubilizing agents:
Other examples are Sucrose
monoesters, Lanolin esters etc.
It has generally been found
that surface-active-agents having HLB (Hydrophilic Lipophilic Balance) values
higher than 15 acts better as solubilizing agents.
COMPLEXATION
|
Solubility of a compound may be increased by complexing
with a complexing agent. e.g. solubility of para amino benzoic acid (PABA) may
be increased by complexing with caffeine.
When an insoluble compound forms a complex which is more
soluble in the solvent - the total solubility is equal to the inherent
solubility of the uncomplexed drug plus the concentration of drug-complex in
solution.
When a certain amount of drug is
mixed in water some amount will get dissolved (A) and some amount will remain
undissolved. If a complexing agent is added to it some drug will be complexed
and become soluble in water. So the total solubility will be will be increased.
When more complexing agent is
added total solubility will increase; at a certain concentration of complexing
agent the solution will become saturated with respect to free drug and the
complex (B). After this point if still complexing agent is used then remaining
drug (undissolved) will form complex and the excess complex will be
precipitated (C). When no drug is left for complexation, complexes of higher
order may be formed.
e.g. I2
is sparingly soluble in water. To dissolve it KI (potassium iodide) is added which makes a complex KI.I2
(i.e. KI3). After point C it forms KI. 2I2, KI.3I2
etc.
HYDROTROPHY
The term hydrotrophy has been used to designate the
increase in solubility in water of various substances due to the presence of
large amounts of additives.
Mechanism
of action
Not clear yet. Some workers have speculated that this
phenomenon is more closely related to complexation involving a weak interaction
between the hydrotrophic agent and the solute.
Another view is that
the phenomenon must be due to change in solvent character because of the
large amount of additive needed to bring about the increase in solubility.
Examples
Since a large
concentration of hydrotrophic agent is required (in the range of 20 to 50%) to
produce a modest increase in solubility, hence its pharmaceutical applications
are very less in number.
Drug
|
Hydrotrophic agent
|
1.
Benzoic acid
2.
Theophylline
3.
Iodine
4.
Adrenochrome mono semicarbazone
|
Sodium benzoate
Sodium acetate and sodium
glycinate
Polyvinyl pyrrolidone
(PVP)
Sodium salicylate
|
SOLVENTS FOR ORAL
PREPARATIONS
The solvents those are usually used in the oral liquid
preparations are purified water, alcohol, glycerin and propylene glycol.
PURIFIED WATER (H2O)
Naturally occurring water exerts its solvent effect on
most substances. In oral preparations the water used is potable water or
Purified Water USP.
Specifications
of Purified Water USP
Method of preparations : By
distillation or by ion-exchange.
Total solid : Less than 10 parts per million (ppm)
pH : Between
5 and 7.
ALCOHOL (ETHANOL)
Next to water, alcohol is
the most useful solvent in pharmacy.
·
It is used as a primary solvent for many organic
compounds.
·
With water it acts as a cosolvent and increases the
solubility of drugs. Alcohol is often preferred because of its miscibility with
water and its ability to dissolve many water-insoluble ingredients, including
drug substances, flavorants, and antimicrobial preservatives.
·
Alcohol is frequently used with other solvents, as
glycols and glycerin, to reduce the amount of alcohol required.
·
It also is used in liquid products as an
antimicrobial preservative alone or as a co-preservative with parabens,
benzoates, sorbates and other agents.
Disadvantages
It produces pharmacologic
and potential toxic effects of alcohol when ingested in pharmaceutical products
particularly by children. Hence, it should not be given to children below 6
years. For OTC (over the counter) oral product for children the recommended
alcohol-content limit is 0.5 %.
Age of the patient
|
Permitted alcohol content
|
For children below 6 years
For children between 6-12
years
Children over 12 years and
adults
|
0.5 %
5.0 %
10.0%
|
 |
GLYCERIN (Glycerol)
·
Glycerin is a clear syrupy liquid with a sweet
taste.
·
It is miscible both with water an alcohol.
·
Glycerin has preservative qualities.
Disadvantages
 |
As a solvent, it is comparable to alcohol, but because of
its viscosity, solutes are slowly soluble in it unless it is rendered less
viscous by heating.
PROPYLENE GLYCOL
It is a viscous liquid, is miscible with water and
alcohol. It is useful solvent with a wide range of application and is
frequently substituted for glycerin in pharmaceutical formulation.
BUFFERS
A buffer is a compound or mixture of compounds that, by
its presence in solution, resists changes in pH upon addition of small
quantities of acid or base.
Buffering agents are necessary to resist the change of pH
upon dilution or addition of acid or alkali in the liquid preparation.
The usual buffering agents used in oral liquid
preparations are acetate buffer and phosphate buffer.
Buffer
|
Mixture
of
|
Buffering
Range
|
Acetate buffer
Phosphate buffer
|
Glacial acetic acid
Potassium, sodium,
ammonium salt of acetic acid
Potassium dihydrogen
phosphate
Di-sodium hydrogen
phosphate
|
pH 2.8 to 6.0
pH 2.0 to 8.0
|
Buffering is required to:
1. Keeping weakly
acidic or basic drug in solution
2. Increase the
stability of the drug
3. Resist the change
of pH upon dilution or addition of acid or alkali (e.g. leaching or alkali from
glass container).
SWEETENERS
Solutions come in immediate contact with the taste buds
(on the tongue). Drugs and other adjuvants are generally not good to taste
(i.e. not palatable). To enhance palatability and to mask the taste of the
drugs etc. sweeteners are used.
Example: Sucrose
(sugar), saccharin, aspartame, liquid glucose.
Sucrose
Source Commercially sucrose is obtained
from sugarcane, beet root and shorgum.
Advantages
1. It is soluble in
aqueous medium.
2. It is available
in highly purified form at reasonable price.
3. It is chemically
and physically stable in the pH range of 4.0 to 8.0.
4. It is frequently
used in conjunction with sorbitol, glycerin and other polyols.
5. Above 66.7 % mold
growth will not take place.
Disadvantages
Concentration of sucrose solution above 66.7% (w/w) the
sucrose crystallize making the solution hazy (i.e. reducing the gloss of the
solution).
Caps of the containers are
generally found to be locked due to this crystallization. Sorbitol, glycerin or
other polyols are used to reduce the crystallization.
Liquid
Glucose
Liquid glucose is an extremely viscid substance that
imparts both body (i.e highly viscous) and sweetness to liquid formulations.
Preparation Partial hydrolysis of starch with strong
acid produce liquid glucose. Its main component is dextrose and maltose.
 |
Saccharin
(Sodium
and Calcium salts are soluble)
Advantages
1. Saccharin is used
to supplement sugars and polyols as sweeteners.
2. It is
approximately 250 to 500 times as sweet as sugar.
3. It has no calorie
value, hence can be given to obese patients and diabetic patients.
Disadvantages
It has a bitter after taste.
Aspartame
 |
Aspartame is the methyl
ester of aspartic acid and phenylalanine.
Advantages
1. It is
approximately 200 times sweeter than sugar.
2. No bitter after
taste.
3. Solubility in
water is adequate for formulation purpose.
Disadvantage
Although it is very stable
as dry powder, its stability in aqueous solutions is pH and temperature
dependent. it is stable at pH between 3.4 and 5.0 and at refrigerated
temperature.
COLORANTS
To enhance the appeal of the vehicle, a coloring agent is
generally used which matches well with the flavour employed in the preparation
e.g. green with mint, brown with chocolate flavor etc. The colorant used is
generally water soluble, non-reactive with other components, and color-stable
at the pH range and under the intensity of light that the liquid preparation is
likely to be exposed during its shelf-life.
N.B. From the psychological
point of view the scheme may be as follows:
Color Red Orange Yellow Green Blue Violet
Psychological
reactions Exciting Cheerful Tranquilizing Subduing
Desirable
properties of a coloring agent
1. Must be harmless,
should have no physiological activity
2. It should be a
definite compound because then its coloring power will be reliable, its assay
practicable.
3. Its tinctorial
(coloring ) power should be high so that only small quantities are required.
4. It should be
unaffected by light, temperature, micro-organisms, pH changes.
5. It should not
interfere with other adjuvants.
6. I must be free
from objectionable odour and taste.
7. it must by
inexpensive.
Example
·
Coal tar colors e.g.
Amaranth
·
The permitted colors do not always give satisfactory
shades when used alone but most popular tints and shades can be obtained by
blending
e.g. Green S and Tartrazine Solution B.P.C. contains
GreenS (greenish blue) and Tartrazine (Yellow green)
PRESERVATION
Specific organisms generally recognized as undesirable in
oral liquids include Salmonella species,
Escherichia coli, Enterobacter species, Pseudomonas species (commonly Pseudomonas aeruginosa), Clostridium and Candida albicans.
Source
of contamination:
Raw materials, processing containers and equipment, the
manufacturing environment, operators, packaging materials and the user.
Characteristics
of an ideal preservative
1. It must be
effective against a broad spectrum of microorganisms.
2. It must be
physically, chemically and microbiologically stable for the life-time of the
product.
3. It must be
nontoxic, non-sensitizing, adequately soluble, compatible with other formulation
components, and acceptable with respect to taste and odour at the
concentrations used.
Some
pharmaceutically useful preservative
Class
|
Preservative
|
Usual
concentration (%)
|
Acidic
|
Phenol
Chlorocresol
o-Phenyl phenol
Alkyl esters of
parahydroxy benzoic acid
(e.g. Methyl and Propyl
Paraben)
Benzoic acid and its salts
Boric acid and its salts
Sorbic acid and its salts
|
0.2 - 0.5
0.05 - 0.1
0.005 - 0.01
0.001 - 0.2
0.1 - .0.3
0.5 - 1.0
0.05 - 0.2
|
Neutral
|
Chlorbutanol
Benzyl alcohol
b-Phenyl ethyl alcohol
|
0.5
1.0
0.2 - 1.0
|
Mercurial
|
Thiomersal
Phenyl mercuric acetate
and nitrate (PMA & PMN)
Nitromersol
|
0.001 - 0.1
0.002 - 0.005
0.001 - 0.1
|
Quarternary ammonium
compounds
|
Benzalkonium chloride
Cetylpyridinium chloride
|
0.004 - 0.02
0.01 - 0.02
|
Preservatives
|
Uses
|
Acidic
Phenol
Alkyl esters of
parahydroxy benzoic acid
(e.g. Methyl
and Propyl Paraben)
Sodium salt of
benzoic acid
Sodium salt of
sorbic acid
Neutral
Chlorbutanol
Benzyl alcohol
b-phenyl ethyl alcohol
Mercurials
Quartenary
ammonium compounds
|
Have characteristic odor and unstable when exposed to oxygen, hence
used rarely.
Mostly used
Adequately soluble in water
Have both antifungal and antibacterial activity
Methyl & Propyl ester at a ratio of 10 to 1 produce a synergistic
effect.
Mostly used
Have antibacterial action
and antifungal action
Water soluble
The are volatile alcohols,
hence, have odor and loss of preservative action on aging.
Not used in oral liquid
preparations.
Used in ophthalmic, nasal
and parenteral products.
Not used in oral liquid
preparations
Used in ophthalmic, nasal
and parenteral products.
Disadvantage: Mercurials
readily reduced to free mercury.
Not used in oral
preparations
Used in ophthalmic, nasal
and parenteral solutions.
Disadvantages: They are
inactivated by variety of anionic substances.
|
SYRUPS
Syrups containing approximately 85% sucrose resist
bacterial growth by virtue of their exosmotic effect on micro-organisms. Syrups
that contain less than 85% sucrose, a sufficient concentration of polyol (e.g.
sorbitol, glycerin, propylene glycol or polyethylene glycol) should be added to
have the required osmotic pressure.
It is possible, however, for surface dilution to take
place in a closed container as a result of solvent evaporation followed by
condensation, with the condensate flowing back onto the liquid surface. The
resulting diluted medium for bacterial and fungal growth. A sufficient
concentration of preservative or 5 to 10% ethanol should be added to arrest the
growth of microorganisms.
FLAVORS
An objectionable taste may lead to nausea, vomiting and
refusal to take the preparation regularly or at all. On the other hand, an
attractive flavour will encourage continuation of treatment.
The four basic taste sensations are salty, bitter, sweet
and sour. A combination of flavoring agents is usually required to mask these
taste sensations effectively.
Flavor
selection
Taste sensation
|
Recommended
flavor
|
Salty
Bitter
Sweet
Sour
|
Butterscotch, maple,
apricot, peach, vanilla, wintergreen mint.
Wild cherry, walnut,
chocolate, mint combinations, anise etc.
Fruit and berry, vanilla
Citrus flavors, liquorice,
root beer, raspberry
|
Flavor
adjuncts
Menthol, chloroform and various salts frequently are used
as flavor adjuncts.
Menthol and chloroform are
sometimes referred to as desensitizing
agents. They impart a flavor and odor of their own to the product and have
a mild anaesthetic effect on the sensory receptor organs associated with taste.
MANUFACTURING CONSIDERATION
Raw
materials
1. Incoming raw materials
should be tested against some specifications
regarding identity, purity, uniformity and freedom from excessive microbial
contamination.
2. Additional processing may be required e.g.
size-reduction or sterilization before manufacturing. It is usually much easier
to begin with low microbial counts in the raw materials than to try to reduce
these counts substantially during processing.
3. In oral liquid
preparations water is the main
vehicle. It should meet the USP requirements for Purified water. It may be obtained by distillation or ion-exchange
treatment. To reduce the microbial burden water is passed through UV-rays and
constant circulation in piping systems that have “dead ends” where
micro-organisms can thrive.
EQUIPMENTS
The following types of
equipments may be used in the manufacture of oral liquid solutions:-
1. Mixing tanks (SS
316 Stainless Steel) equipped with an
agitator.
2. Measuring devices
for large and small amount of solids and liquids.
3. A filtration
system for the final polishing - e.g. Sparkler filter.
Cleaning
of equipments
All equipments must be
thoroughly cleaned and sanitized before use.
Disinfectants
used: Dilute solutions of H2O2,
phenol derivatives and paracetic acid.
Sterilized
by: Alcohol, boiling water,
autoclaving, steam or dry heat.
Material
of construction
·
Tanks are usually
constructed of polished stainless steel and are usually jacketed to allow for
heating or cooling of the contents.
·
Tanks are covered and equipped with see-through
charging ports and illumination for easy observation of the contents. If the
tanks are used for compounding of the bulk liquid, they have a built in
agitation system.
·
The compounded liquid may then be transported to the
filling line, either manually by filling into portable transport tanks (fitted
with wheels) or by pumping (or gravity flow) through a liquid delivery conduit.
·
All the equipments and pipe lines should be easy to
disassemble, clean and sanitise.
COMPOUNDING PROCEDURE
Objective Complete solution should usually be
confirmed at every stage in the manufacture of a homogeneous liquid.
Formula
1. Active
constituent / Drug
2. Vehicle (Water /
Alcohol / Glycerol)
Sweetening agents (viscosity building agents) Syrup, Sorbitol, Glycerol
3. Preservatives
4. Flavors
5. Colors (Dyes)
Steps
of preparation
1. Purified water is
heated to approximately 500C to facilitate the dissolution of the
solid solutes. Solid solutes are added to the warm water and stirred to
dissolve (e.g. sugar, drug).
2. If any additive
is required in small amount then it should be dissolved separately and then
mixed with the bulk mixture.
3. Any large volume
liquids (e.g. glycerol, sorbitol solution) are added and mixed until
homogeneous.
4. Before adding
flavors the temperature should be reduced to 300C (since most of the
flavors are volatile). The flavor should be dissolved in small amount of
alcohol (since flavors are generally insoluble in aqueous medium) and then it
is mixed with the bulk mixture.
5. Dye should be
dissolved n small amount of water. Then transferred to the bulk mixture.
6. Finally volume is
made up to the required volume. The total mixture is agitated thoroughly until
homogeneity is obtained.
7. Finally the batch
is filtered to obtain a polished, clear solution.
ORAL SOLUTIONS
Liquid system where all the solutes remain in dissolved
state is known as solution. Solutions
intended to be taken orally is called oral
solutions.
Advantages
1. Absorption is
instant from the gastro-intestinal tract.
2. Uniform dosage is
certain.
3. They provide a
safe means of administering substances like potassium iodide that cause gastric
pain if taken dry, e.g. as powders or tablets.
4. The attractive
appearance of a solution in a well polished bottle has a beneficial
psychological effect.
PREFORMULATION
Oral solutions contain
1. Active
constituents (Water soluble)
2. Preservative
3. Flavorant
4. Colorant
5. Chemical
stabilizers (Antioxidant, reducing agent, synergists)
Dose
Liquid pharmaceuticals for oral administration are
usually formulated such that the patient receives the usual dose of the
medication in a conveniently administered volume, as 5 ml (one teaspoonful), 10
ml or 15 ml (one table-spoonful).
On the other hand many solutions used in paediatric
patients are given by drop, utilizing a calibrated dropper usually furnished by
the manufacturer in the product package.
Calculation
The strengths of
pharmaceutical preparations are usually expressed in terms of % strength (w/w,
w/v, v/v).
Formulation
Some chemical agents may be
slowly soluble. In this case rate of dissolution may be enhanced by
1. application of
heat: the temperature should not destroy other ingredients.
2. decrease the
particle size to increase the specific surface area.
3. by agitation: but
dissolution is delayed compared to heat application.
Chemical
interaction
Chemical interactions which may occur between the various
components of a solution which may result in a alteration in the preparation’s
stability and / or potency. For example, it has been demonstrated that esters
of p-hydroxy benzoic acid (methyl-, ethyl-, propyl- and butyl- parabens)
frequently used preservatives in oral preparations, have a tendency to
partition into certain flavoring oils.
SYRUPS
·
Syrups are
concentrated, aqueous preparations of a sugar or sugar-substitute with or
without added flavoring agents and medicinal substances.
·
Syrups containing flavoring agents but not medicinal
substances are called flavored vehicles (syrups).e..g Cherry Syrup,
Cocoa Syrup, Orange syrup, Raspberry Syrup.
·
Syrups containing medicinal agents are called medicated syrups. e.g. Chlorpheniramine
maleate syrup, Ipecac syrup, Chloral hydrate syrup etc.
Components
of syrups
Most syrups contain the following components in addition
to the purified water and any medicinal agents present:
1. the sugar,
usually sucrose, or sugar substitutes used to provide sweetness and viscosity,
2. antimicrobial
preservatives,
3. flavorants, and
4. colorants.
Sucrose
and non-sucrose based syrup
Sucrose is most frequently employed in syrups. In special
circumstances it may be replaced by sugars, such as, dextrose, or non-sugars as sorbitol,
glycerin and propylene glycol.
Methyl cellulose or hydroxyethyl cellulose -these two materials are not
hydrolyzed and absorbed into the blood stream, and their use results in an
excellent syrup-like vehicle.
Taste
masking by syrup
The syrup imparts a characteristics “body” (viscosity)
and together with the sweetness and the flavorants results in a type of
pharmaceutical preparation that is quite effective in making the taste of added
medicinal agents. When the syrup is swallowed, only a portion of dissolved drug
actually makes contact with the taste buds, the remainder of the drug being
carried past them and down the throat in the containment of the viscous syrup.
In the case of antitussive syrups (e.g. linctus) the
thick sweet syrup has a soothing effect on the irritated tissues of the throat
as it passes over them.
Preservative
action of syrup
Simple syrup NF contains 85% w/v sucrose. At this
concentration the syrup is resistant to microbial growth, due to unavailability
of the water required for the growth of micro-organisms.
85% w/v syrup has a specific gravity of 1.313
i.e. 100 ml
syrup contains 85 gm sucrose
Weight of 100 ml
syrup = 100 x 1.313 =
131.3 gm
\ Weight of water present in 100 ml syrup = (131.3 - 85) gm
=
46.3 gm
Volume of water
present in 100 ml syrup =46.3 ml
\ Volume of sucrose present in 100 ml syrup = (100 - 46.3) ml
=
53.7 ml
\ 100 ml 85% syrup contains
Weight
|
Volume
|
|
Sugar
Water
|
85.0
g
46.3
g
|
53.7
ml
46.3
ml
|
Syrup (total)
|
131.3
g
|
100.0
ml
|
The solubility
of sucrose in water is 1 g in 0.5 ml
\ to dissolve 85 g sugar required will be = 85 x 0.5 ml
=
42.5 ml
Thus, only a very slight excess
of water (46.3 - 42.5 = 3.8 ml per 100 ml of syrup) is
employed in the preparation of syrup. The sight excess of water permits the
syrup to remain physically stable under conditions of varying temperature.
If the syrup were completely saturated with sucrose,
under cool storage conditions some sucrose might crystallize from solution and,
by acting as nuclei, initiate a type of chain reaction that would result in the separation of an
amount of sucrose disproportionate to its solubility at the storage
temperature. The syrup would then be very much unsaturated and probably
suitable for microbial growth. However, the syrup NF is stable and resistant to
crystallization as well as to microbial growth.
Preparation
of Syrups
Syrups are frequently prepared by one of four general
methods; depending upon the physical and chemical characteristics of the
ingredients.
1. Solution of the
ingredients with the aid of heat
2. Solution of the
ingredients by agitation without the use of heat
3. Addition of
sucrose to a prepared medicated liquid or to a flavored liquid and
4. by percolation of
either the source of the medicating substance or of the sucrose.
Solution
with the aid of heat
The sugar is generally added to the purified water, and
heat is applied until solution is effected. Then other required heat-stable
components are added to the hot syrup, the mixture is allowed to cool, and its
volume is adjusted to the proper level by the addition of Purified Water.
The use of heat facilitates the rapid solution of the
sugar as well as certain other components of syrups.
If excessive heating occurs
then sucrose may be hydrolyzed into dextrose (D-glucose), and fructose
(levulose). This hydrolytic reaction is referred to as inversion, and the combination of the two monosaccharides is invert sugar. When heat is applied in
the preparation of a sucrose syrup, some inversion of the sucrose is almost
certain. The speed of inversion is greatly increased by the presence of acids,
the hydrogen ion acting as a catalyst to reaction.
Invert sugar is more sweeter than sucrose, and normally
colorless. Syrup darkens due to the effect of heat on the fructose. When the
syrup is greatly overheated, it becomes amber colored due to the caramelization
of the sucrose. Syrups so decomposed are more susceptible to fermentation and
microbial growth.
Because of the prospect of decomposition by heat, syrups cannot
be sterilized by autoclaving.
Solution
by agitation without heat
Sucrose and other formulation agents may be dissolved in
purified water by placing the ingredients in a vessel of greater capacity than
the volume of syrup to be prepared, thus permitting the thorough agitation of
the mixture.
Addition
of sucrose to a medicated liquid or to a flavored liquid
Medicated liquid such as tincture or fluid extract is
employed as the active ingredient in the preparation of syrup.
If the extract contains alcohol soluble ingredients and
the alcohol amount is high then sucrose is added directly and stirred.
If alcohol content is low and all the ingredients are
water soluble then the liquid extract is directly mixed with a prepared syrup.
Preparation
of syrup by percolation
In this method purified
water or an aqueous solutionis passed slowly through a bed of crystalline
sucrose, thus dissolving it and forming the syrup. If required a poriton of the
percolate is recycled.
Preparation of a
multivitamin syrup
Formula: Each 15 ml contains
Active ingredients Vitamin B1 4.5 mg
Vitamin B2 2.5 mg
Vitamin B6 1.5 mg
Niacinamide 30 mg
D-Pantothenol 5 mg
Sweeteners Sorbitol 1
gm
Glycerin 0.5 gm
Sugar 7 gm
Preservative Sodium benzoate 0.016 % (w/v)
Methyl paraben sodium 0.015 % (w/v)
Propyl paraben sodium 0.0015%(w/v)
Stabilizer Disodium edetate 0.008%
Taste enhancer Citric acid 0.008% (w/v)
Flavours q.s.
Colours Caramel q.s.
Vehicle Purified water 15 ml
Procedure
1. Primary Syrup is
prepared as usual, filtered and cooled to room temperature. The material is
transferred to the mixing tank and stirring is started.
2. Vitamin B1 is
dissolved in small volume of water and added to the syrup.
3. Vitamin B2 is
slightly soluble in water, hence, it is dissolved with the aid of 10% sodium
hydroxide. Vitamin B6 is also added to dissolve. The mixture is transferred to
the mixing tank.
4. Niacinamide is
dissolved in small amount of water and added to the mixing tank.
5. D-pantothenol is
dissolved in hot water, cooled and transferred to the syrup.
6. Sorbitol and
glycerin are added.
7. All the
preservatives are dissolved in small volume of water and added to the syrup.
8. Citric acid and
disodium edetate is dissolved separately in water and then mixed to the syrup.
9. Flavors and color
are added and the final volume is made up with water.
10. Mixed for 2 hours
and filtered.
